ATAT1

Researchers analyzed mRNA expression patterns to reveal a complex mechanism that could ultimately be exploited to treat Alzheimer's disease. Researchers have uncovered yet another potential treatment mechanism in the quest to find new therapies for Alzheimer’s disease. In an article published March 7 in PLOS Biology, scientists from China’s Air Force Medical University described how they created a mouse model of Alzheimer’s with a gene change that ultimately led myeloid cells to infiltrate the brain, where they matured into immune cells called macrophages—which then consumed the disease’s characteristic amyloid-beta plaques. This improved cognition in the mice compared to genetically normal Alzheimer’s models. Some clinical trials are investigating amyloid-beta targeting drugs for early Alzheimer’s, the researchers wrote in their paper, adding “our results may supply a new choice for treatment strategies.” The gene at the heart of the study encodes the enzyme METTL3. METTL3 is an RNA N6-methyladenosine, or m6A, methyltransferase. It regulates gene expression by performing what’s known as m6A methylation on many different types of RNA, including mRNA. While previous research showed that normal METTL3 function plays a key role in long-term memory consolidation in the hippocampus, another study published in 2020 showed that it was expressed at higher levels in mouse models of Alzheimer’s compared to controls. This suggested that m6A methylation of RNA might be playing a role in the disease. To find out if that was the case, the researchers developed a mouse model without the gene for METTL3 in myeloid cells, which are cells derived from bone marrow that go on to form different types of blood and immune cells. The team focused on myeloid cells specifically because recent research has shown that the cells can cross the blood-brain barrier and differentiate into macrophages, according to the paper. These so-called “blood-derived macrophages” are thought to work with the brain's resident immune cells, microglia, on a variety of processes, from neurodegeneration to repairing and protecting the central nervous system from damage.   The researchers then injected amyloid-beta plaques in the brains of their new models and a cohort of unaltered mice to induce Alzheimer's and put them through a pair of maze tests to assess their cognitive function. Seeing that the METTL3-deficient group performed better than their counterparts, they replicated their results by transplanting bone marrow from genetically unaltered and METTL3-knockout models into two more groups of mice, inducing Alzheimer’s in all of them and having them perform the same tests. The mice who received bone marrow from the METTL3-knockout mice outperformed the ones who received it from wild-type models. Together, the results suggested that inhibiting METTL3 slowed Alzheimer’s progression, the researchers wrote. Next, the team took a closer look at what was happening in the METTL3-deficient cells. Based on a previous study showing that a cellular process called microtubule acetylation might play a role in neurodegenerative disease, they compared the microtubules of wild-type macrophages to those without METTL3. The microtubules of METTL3 knockout cells had less acetylation than the ones in wild-type cells, along with lower expression of a key gene involved in the process, ATAT1. But further analyses showed that METTL3 didn’t directly impact ATAT1 expression, which meant the researchers must be missing a puzzle piece.   More analyses of mRNA expression patterns revealed it. They found that under normal conditions, METTL3 regulates the expression of another gene, DNMT3A, through m6A methylation. This is carried out with the help of a reader protein, a type of protein that recognizes and binds to modified DNA or RNA—in this case, one that specifically recognizes mRNAs that have undergone m6A methylation. DMT3A expression increases ATAT1 expression, which leads to microtubule acetylation. But without METTL3, there wasn’t enough reader protein activity for DMT3A to be expressed—thus inhibiting ATAT1 and microtubule acetylation. Further experiments showed that the lack of microtubule acetylation prompted the myeloid cells to enter the brain, where they matured into macrophages and destroyed the amyloid-beta plaques. This, in turn, improved the models’ cognition. While the complex mechanism leaves many open questions, it does suggest that targeting m6A methylation could be a route for treating Alzheimer’s disease. Given that mRNA methylation is an important process for gene regulation, future research would need to figure out where along the pathway they could intervene without causing side effects. The road to treating Alzheimer’s has been paved with failures, though there have been a couple of recent wins. In the few years, the FDA has approved two drugs for early, mild disease. Both are monoclonal antibodies, both were developed by Biogen and Eisai, and neither is without controversy. Aducanumab, trade name Aduhelm, got the FDA green light in June 2021 despite concerns that there wasn’t enough evidence that it worked, while lecanemab, or Leqembi, was approved this past January with still-unanswered questions about its safety.

Reducing the methylation of a key messenger RNA can promote migration of macrophages into the brain and ameliorate symptoms of Alzheimer's disease in a mouse model, according to a new study. The results illuminate one pathway for entrance of peripheral immune cells into the brain, and may provide a new target for treatment of Alzheimer's disease. Reducing the methylation of a key messenger RNA can promote migration of macrophages into the brain and ameliorate symptoms of Alzheimer's disease in a mouse model, according to a new study publishing March 7 in the open access journal PLOS Biology by Rui Zhang of Air Force Medical University in Xian, Shaanxi, China. The results illuminate one pathway for entrance of peripheral immune cells into the brain, and may provide a new target for treatment of Alzheimer's disease. A presumed trigger for the development of Alzheimer's disease is the accumulation of proteinaceous, extracellular amyloid-beta plaques in the brain. High levels of amyloid-beta in mice leads to neurodegeneration and cognitive symptoms reminiscent of human Alzheimer's disease, and reduction of amyloid-beta is a major goal in development of new treatments. One potential pathway for getting rid of amyloid-beta is the migration of blood-derived myeloid cells into the brain, and their maturation into macrophages, which, along with resident microglia, can consume amyloid-beta. That migration is a complex phenomenon controlled by multiple interacting players, but a potentially important one is the methylation of messenger RNA within the myeloid cells. The most common type of mRNA methylation, called m6A, is carried out by the enzyme METTL3, so the authors first asked whether deficiency of METTL3 in myeloid cells had any effect on cognition in the Alzheimer's disease mouse model. They found that it did -- treated mice performed better on various cognitive tests, an effect that could be inhibited when they blocked the migration of myeloid cells into the brain. How did decreased mRNA methylation promote myeloid cell migration? The authors elucidated a complex mechanism. Through analysis of mRNA expression patterns and other techniques, they showed that depletion of METTL3 reduced the activity of a key m6A reader protein, which recognizes m6A-modified mRNAs and promotes their translation into protein. That led to a decline in another protein, and that inhibited the production of yet another protein, called ATAT1. Loss of ATAT1 reduced the attachment of acetyl groups to microtubules, and that reduction in turn promoted migration of the myeloid cells into the brain, followed by maturation into macrophages, increased clearance of amyloid-beta, and improved cognition in mice. "Our results suggest that m6A modifications are potential targets for the treatment of Alzheimer's disease," the authors concluded, while noting that much about this pathway in Alzheimer's disease remains to be explored. Because mRNA methylation has a fundamental effect on a wide variety of downstream targets, effective drug development within this pathway may require moving further downstream to avoid unwanted effects.